Original article
Studies of trypanocidal (inhibitory) power of naphthoquinones: Evaluation of quantum chemical molecular descriptors for structure–activity relationships

https://doi.org/10.1016/j.ejmech.2007.12.023Get rights and content

Abstract

Electronic, lipophilic and steric descriptors included in QSAR-2D and -3D are analyzed for a set of ortho- and para-naphthoquinones that have proved to be powerful oxidative agents with potent trypanocidal activities specially against Leptomonas seymouri and Trypanosoma cruzi. Electronic properties are calculated by means of semiempirical (PM3), ab initio (HF/3-21G) and density functional theory (B3LYP/6-31 + G) methodologies. Three different electronic states, neutral quinones, hydroquinones and semiquinones, are studied to investigate if any one of them are statistically related with the biological activities. The best correlations were obtained at the B3LYP level of theory because it includes electronic correlation.

The QSAR-2D indicates that the best trypanocidal growth inhibitors are molecules in the semiquinone electronic state, with the following properties: (a) high negative value of EHOMO, (b) high negative charge in the oxygen atoms of the carbonyl groups, (c) high positive charge in the carbon atom of one of carbonyl moieties and (d) high electronegativity (χ). In a complementary way, the QSAR-3D indicates that the electrostatic field correlates with trypanocidal activity and the presence of bulk moieties would increase activity.

The idea of comparing the three electronic states may prove to be of most importance in the general strategy to the design of new trypanocidal drugs. In fact, the experimental results showed that semiquinone is the one really statistically relevant indicating a clear connection between biochemical and theoretical aspects. Finally, we demonstrated that to be a good anti-trypanosomatid compound, the molecule must be a good electron acceptor to reach easily the essential semiquinone state. We expect that the present results motivate new experimental as well as theoretical investigations that confirm our findings.

Graphical abstract

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QSAR-2D and -3D treatments were made with a set of trypanocidal ortho- and para-naphthoquinones. The results indicate that the inhibitory activity of the tripanosonatids′s growth is related to the semiquinone electronic state. The inhibitory activity increases as a function of the following factors: (i) a more negative value of the EHOMO; (ii) an increase of the negative charge of atoms O1 and O2 (red field) and of the positive charge QC1 (blue field) and (iii) with an increase in the electronegativity (χ).

Introduction

Quinones have been proposed as trypanocidal, cytostatic and antiviral agents [1], [2], [3], [4], [5], [6]. The o-naphthoquinones, especially β-lapachone, α-lapachone, mansonones and analogues [7], [8], are trypanosomatid growth inhibitors with high cytotoxic activity. By diverting reducing equivalents they inhibit microsomal lipid peroxidation [7], [8]. Cytosolic and mitochondrial diaphorase (DTD), a quinone oxidoreductase, catalyzes quinones' reduction to hydroquinones via two mono-electronic steps. It has been demonstrated that, in a mixture of hepatic rat cytosol and β-lapachone (or the related o-naphthoquinones named in Fig. 1 as CGx (x = 10-248, 9-442, 8-935)), the o-naphthoquinones produced hydroquinones that in turn form the corresponding semiquinone and reactive oxygen species (ROS) [9], [10] in a so-called oxidative comeback reaction. In another study, the quinones were reduced by ascorbate to semiquinones, followed by a mono-electronic transfer to dioxygen to yield superoxide anion radicals characterized as ROS.

However, in spite of the importance that quinones have in biological chemistry, only little is known about the characteristics of the mechanism that allows them to be good trypanocidal, cytostatic and antiviral agents. Since the mechanisms of reaction involving free radicals are grouped in three typical steps: initiation, propagation and termination (see Scheme 1), we investigated the three electronic states of the selected quinones to shed light into the mechanism of protection. For the later purpose we employed semiempirical, ab initio and DFT methodologies to determine the electronic and structural properties for the three states of the quinones. Then, a first quantitative structure–activity relationship (QSAR-2D) study with a first set of quinones (analogues of the β-lapachone) is performed to test if there is any particular electronic state (neutral quinone, hydroquinone or semiquinone) that would represent the active form of the population of o-naphthoquinones. Because quinones' molecular shape and local electronic properties are usually complementary to the active site of enzymes involved in the oxide-reduction metabolism, we add to our first o-naphthoquinone set, three more sets of o-naphthoquinones and p-naphthoquinones with variations in their shape as well as electronic properties. The structures of four sets are described in the following section and are used in a second QSAR (QSAR-3D (CoMFA)). We expect that the present results motivate new experimental as well as theoretical investigations that confirm our finding.

Section snippets

Molecular systems, synthesis and bioassays

Many sets of ortho- and para-naphthoquinones have been reported [10], [11], [12], [13], [14], [15]; the structures and biological data of that are used in this study.

A set of 11 o-naphthoquinones (Fig. 1) have been proved to be powerful oxidative agents with a well-known action mechanism, in which a semiquinone is an essential intermediate leading to superoxide anion in aerobic conditions (Scheme 1) [10]. All reported experimental biological data (DHLA, IC50 of Leptomonas seymouri and Chritidia

QSAR-2D of the o-naphthoquinone set

A statistical study comparing significance of the semiempirical, HF/3-21G and B3LYP/6-31 + G methodologies was performed by means of PCA and regression analysis of SAMPLE I (Table 2). For the regression analysis presented, seven PCs were taken into account together with a PLS2 method using as dependent variables those previously described (DTT, DHLA, IC50 of L. seymouri).

Once all regression analyses are done, the best model is that in which the L. seymouri activity correlates with the electronic

QSAR-2D of the o-naphthoquinone set

As expressed above, the comparison of three statistical models (neutral, hydroquinone and semiquinone electronic states) using the B3LYP/6-31 + G results have shown the best fitting for the semiquinone electronic state (SAMPLE IIS), taking IC50 of L. seymouri as dependent variable and EHOMO, QC1, QC3, QO1, QO2, polarizability (Pola), log P and χ as independent variables (Fig. 4, Table 3 and Eq. (3))

For the molecule set assayed, EHOMO, QO1 and QO2 have negative values; QC1 has positive values

Conclusions

In the PCA study of the entire o-naphthoquinones, SAMPLE I (Fig. 1), the best regression parameters were obtained when the IC50 of L. seymouri activity was used as dependent variable and the DFT descriptors as independent variables. The correlation for the calibration was 0.97 and for the validation was 0.95 (Table 2).

When the quinones were grouped into three different samples (neutral, semiquinones and hydroquinones; SAMPLE IIN, SAMPLE IIS and SAMPLE IIH) the same procedure is applied and new

Acknowledgements

This work was supported by the ChagaSpace project, LFMMB, Fac. Química. Gral. Flores 2124, 11600 Montevideo, Uruguay. MP and MD thanks AUGM (Asociación de Universidades Grupo Montevideo).

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